delta-alkenyl cyanoacetic esters and method of producing same



Patented June 7, 1938 UNITED STATES PATENT OFFICE A1-ALKENYL CYANOACETIC ESTERS AND METHOD OF PRODUCING SAlVIE of Maryland (1929) No Drawing. Application October 15, 1936, Serial No. 105,822

15 Claims.

This invention relates to new derivatives of cyanoacetic esters. It relates more particularly to A1-alkenyl cyanoacetic esters, and includes not only these new products, but also the novel process by which they may be produced.

The new compounds with which this invention is concerned may be represented by the following graphic formula:

in which R is a A1-alkenyl radical, which may be primary or secondary, R1 is an alkyl radical, an aralkyl radical, an aryl radical, a cyclohydrocarbon radical, such as cyclohexyl or cyclopentyl, or other hydrocarbon or substituted hydrocarbon radical, and R2 is an alkyl radical, or the like. The A1-alkenyl group, represented by R, in general has the following structure:

R4O=C- in which any two of the radicals R3, R4 and R5 may be hydrogen, but at least one of them must be an alkyl group, saturated or unsaturated. If R3 is hydrogen, the A1-alkenyl group is referred to herein as a primary Ai-alkenyl group; if R3 is an alkyl group, the Ai-alkenyl group is referred to herein as a secondary A1-alkeny group.

The new products are advantageously prepared by the alkylation of the corresponding alkylidene cyanoacetic esters, in the course of which the double bond uniting the alkylidene group and the cyanoacetic ester group is shifted to the A1 position, so that the alkylidene group is changed, by isomerization or other means, to the corresponding alkenyl group with the double bond in the A1 position, as shown in the equation:

R R. R1. R. ON

COOEt COOEt The A1-alkenyl group in these alkenyl cyanoacetic esters can vary widely, as all of the primary and secondary alkylidene cyanoacetic esters, with the exception of the ethylidene compound, can be readily transformed into corresponding Ai-alkenyl cyanoacetic esters by the novel process of this invention, and the range of alkenyl esters which may be produced is limited only by the availability of the various alkylidene cyanoacetic esters.

The Ai-alkenyl cyanoacetic esters, whether the alkenyl group is primary or secondary, are new products, many of which, particularly the primary derivatives, are useful as intermediates for the production of A1-alkenyl barbituric acids and thiobarbituric acids, by the condensation of urea or thiourea with the corresponding cyanoacetic ester, with subsequent replacement of the imino group, by an oxygen atom, by hydrolysis; and are also useful for the production of unsaturated acids, by the removal of the nitrile group.

In accordance with the process of the invention, the alkylidene cyanoacetic esters may be subjected, in solution, to alkylation with a suitable alkyl or aralkyl halide, sulfate, 'or other salt, in the presence of a sodium alkoxide, such as sodium methoxide or sodium ethoxide. In the reaction which takes place, the double bond of the alkylidene cyanoacetic ester shifts to the A1 position in the alkenyl group, and the alkyl or aralkyl group of the halide, sulfate or other salt becomes attached to the methylene carbon of the malonic ester.

The invention will be further illustrated by Into a suitable reaction vessel equipped with a mechanical stirrer, a reflux condenser, a dropping funnel and a thermometer are placed 300 parts of dry ether, containing 33.1 parts of 'so-" dium ethoxide. C. by means of an ice-salt mixture and 105 parts of l-n-propyl-butylidene cyanoacetic ester are slowly added, with agitation, at such a rate that the temperature of the mixture does not rise above 0 C. After all of the ester has been added, the stirring is continued for some time and then 85 parts of diethyl sulfate are added in one portion. The molar ratio of the cyanoacetic ester and the diethyl sulfate used is 10 to 11. After the diethyl sulfate is added, the cooling bath is removed and the reaction mixture is rapidly warmed to the refluxing temperature, at which time a more or less vigorous reaction takes place. Care should be taken that the reaction is not allowed to proceed too rapidly. When the reaction starts, sodium ethyl sulfate precipitates from the solution. The refluxing and stirring are continued for 'about 8 to 14 The solution is cooled below 0 Allyl bromide, 1-n-propylbutylidene c a id tib night. It isthen' diluted with about 2 volumes of water, the organic layer is separated, and the aqueous layer extractedwith several portions of benzene about 300 parts in. all, and the com-' bined organic layer and benzene 'extract are washed with water. movedat somewhat reduced pressure, and the product is purified by distillation. It has a ing range of'11'7 to 119" G114 mm. i

Example 2.Preparation.of l-n propyl Ai-n-Q' .isopropenyl, A1-butenyl pentenyl (normalor iso), A1-hexenyl (normal 'or butenyl allyl cyanoacetic methyl ester, v Q

' CHaCHzCHg OHsOHaCH=C impala-0H, V coo yr methyl ester and sodium methoxide, in approxi- .tions as in Example 1, using methanolasthe BU parts of'allylrbromide, 2815 'pylidene cyanoacetic ester and 12.7 parts 0f"S0-' solvent; The desiredproduct "is 'isolated' and Example 3..Prep aration ofallyl isopropenyl V cyanoacetic ethyl" ester, dragon-0H,-

oN I oHl=o COOEt V OHa s 7 parts of V isoprodium ,ethoxide are reacted in 80 parts'of absolute alcohol, as'in Exampleli The above productis isolated and purifiedv by distillation;

In the processes-f the foregoing", examples, various alkyl or'aralkyl saltsjsuch as the Eu]:

fates, halides, etc. maybeused'for the alkylation of the 'alkylidene *cyanoacetio-esters; with-the production of alkyl Ai-alkenyl cyanoacetic: esters,

in the presenceof sodium methox'i'de or sodium ethoxi'de 'or other jalkoxidesi Where" the halides are used as alkylating agents, it is'preferableto use the :more reactive bromides and iodides,as

they givesomewhat better yields, butth'e: chlo rides may be used if desired. Various solvents,

including inert solvents such as ether, benzene,

etc.,,and the alcohols, such as methanoLabsolute 7 alcohol, propanol, etc, maybe used. Whenalkyl or 'aralkyl sulfates are-usedas alkylating agents; i

such solvents as ether and benzene are preferably used; In general, if an alcohol is used as the'solvent; it is advantageous :to use 'the same alcohol as was usedin esterifying the cyanoaoetic acid,

' cyclopentyl group, etc. V

, flTheialkylidene"cyanoacetic esters, from which 1 the A1ealkenyl alkyl cyanoacetic esters: arepre- To ent'inventiomin'clude both the primary and'sece "ondary alkylidene cyanoacetic esters, which may be produced many suitable 'm'annerybut which to avoid the production of mixed esters;

The groups which may be' so introduced include not only-the primary alkylgroups, but also the secondary; alkyl groups, such as the isopropylqor secondary butyl 1 groups, as 'well *as unsaturated alkylgroups, such' as the allyl,-.crotyl-'or citronellyl' groups, aralkyl groupsgsuch as benzyl and the like, cyclic groups; such as the cyclohexyl or pared in'accordance with the process of the piese:

are most advantageously produced in accordance with the process described in application Serial No. -;825,1filed October'15, 1936, of ArthunC, v

The benzene is then 'reof such compounds .by the condensation of an 1 aldehyde or ketone with cyanoacetic ester in the presence of a soluble salt, a condensing agent,

which gives good results being piperideneacetate.

' Among the new. Al-alkenyl cyanoacetic esters which may be prepared by the process of the present invention, and which are new products, useful as intermediates in the. production of other produetsyare compounds in which the Al-alkenyl radical may be oneof the following: A1-n-propenyl, 7

(normal or iso), A1-

iso) A1,sbutadienyl, A1,w-1,3-dimethy1 octadienyl (citronellenyl) -1-methylA1-n-propenyl, 1-ethyl-.

cyanoacetic radical may be attached to one of,

(normalfiso or secondary) allyl, bfotyLcitroriel:

, butyl-Ai-n pentenyl, and others, and: in which I 'the other linkage of'the methylene carbon of the lyl, cinnamyl, amyl Inormal, iso onsecbhdary),

hexyl 1 (normal, no or secondary), cyclohexyl, 1 7

cyclopentyl, phenyl-ethyl, ,ben'zyl, heptyl (normal, iso or secondary) and others, 1

These new products maybe prepared by other processes than'that described above, for'example, by reacting the alkylidene .cyanoacetic" esters and the alkylating salts inan inert solvent in the presence of metallic sodium. In this application, we claim. the process of producing the new an alkylating agent, suchas an alkyl or aralkyl salt, in the presence of "sodiumjalkoxide, suchas A -alkenyl alkyl, cy'anoacetic esters by the ref action of an 'alkylidene cyanoacetic ester with.

also claimwthe new products; Thefterms' alkenyl yand alkylidene, as usedin this specificationand'the appendedclaims," are to be.con-,

strued in their, narrowsense, as including only may be saturated or..unsaturated.

,Weclaim;

lfin'i-alkenyl cyanoaceti c esters.

esters. 7 r W 7. Compounds of the formula.

J RQ ooom inwhich R1, R2 and R zi' are radicals of the class consisting of hydrogen and alkyl groups, but at least one is alkyl, R4 is a hydrocarbon residue, and'Rs isalk'yl r cyanoa'cetic esters.

10; Allyl isopropenyl 'cyanoacetic esters; n 11. The'process of. preparing Ar-alkenyl"cyanoacetic Jesters which comprises reacting an ialkylie dene cyanoacetic esterwith an'alkyl or aralkyl salt in thepresence of an alkali'metal'alkoxide. 1,12,. The processpipreparing.mealkenyl cyanoopen-chain aliphatic iradicals, although these r 2. Primary Aralkenylcyanoacetic esters, a

aralkyl salt in the presence of an alkali metal alkoXide in an inert solvent.

15. The process of preparing A1-alkeny1 cyanoacetic esters which comprises reacting an alkylidene cyanoacetic ester with an alkyl or aralkyl salt in the presence of sodium ethoxide in an inert solvent.

ARTHUR C. COPE. WALTER H. HARTUNG. FRANK S. CROSSLEY.

DISCLAIMER 2,119,526.Arthm" C. Cope, Bryn Mawr, Pa., Walter H. Hartung, Baltimore, Md., and Frank S. Orossley, Philadelphia, Pa. A1ALKENYL OYANOACETIC ESTERS AND METHOD OF PRODUCING SAME. Patent dated June 7, 1938. Disclajimer filed October 14, 1939, by the assignee, Sharp ct Dohme, Incorpomte 1. Hereby disclaims from claim 11 of said Letters Patent all processes which do not include the preparation of a secondary A -alkenyl cyanoacetic ester by reacting a corresponding alkylidene cyanoacetic ester with an alkyl or aralkyl salt in the presence of an alkali metal alkoxide.

2. Hereby disclaims from claim 12 of said Letters Patent all processes which do not include the preparation of a secondary A -alkenyl cyanoacetic ester by reacting a corresponding alkylidene cyanoacetic ester with an alkyl or aralkyl halide in the presence of an alkali metal alkozn'de.

3. Hereby disclaims from claim 13 of said Letters Patent all processes which do not include the preparation of a secondary A -alkenyl cyanoacetic ester by reacting a corresponding alkylidene cyanoacetic ester with an alkyl or aralkyl salt in the presence of sodium ethoxide.

4. Hereby disclaims from claim 14 of said Letters Patent all processes which do not include the preparation of a secondary A -alkenyl cyanoacetic ester by reacting a corresponding alkylidene cyanoacetic ester with an alkyl or aralkyl salt in the presence of an alkali metal alkoXide in an inert solvent.

5. Hereby disclaims from claim 15 of said Letters Patent all processes which do not include the preparation of a secondary A -alkenyl cyanoacetic ester by reacting a corresponding alkylidene cyanoacetic ester with an alkyl or aralkyl salt in the presence of sodium ethoxide in an inert solvent.

6. Hereby disclaims claims 1, 2, 4, 5, and 7.

[Ofiicz'al Gazette November 7, 1989.] 

